Roles of liver innate immune cells in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease in the United States and other developed countries and is expected to increase in the next few years. Emerging data suggest that some patients with NAFLD may progress to nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. NAFLD can also promote the development and progression of disease in other organ systems, such as the cardiovascular and endocrine (i.e. diabetes) systems. Thus, understanding th...     

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

It is not known why natural killer T (NKT) cells, which modulate liver injury by regulating local cytokine production, are reduced in leptin-deficient ob/ob mice. NKT cells express adrenoceptors. Thus, we hypothesize that the low norepinephrine (NE) activity of ob/ob mice promotes depletion of liver NKT cells, thereby sensitizing ob/ob livers to lipopolysaccharide (LPS) toxicity. To evaluate this hypothesis, hepatic NKT cells were quantified in wild-type mice before and after treatment with NE inhibitors, and in dopamine beta-hydroxylase knockout mice (which cannot synthesize NE) and ob/ob mice before and after 4 weeks of NE supplementation. Decreasing NE activity consistently reduces liver NKT cells, while increasing NE has the opposite effect. Analysis of hepatic and thymic NKT cells in mice of different ages demonstrate an age-related accumulation of hepatic NKT cells in normal mice, while liver NKT cells become depleted after birth in ob/ob mice, which have increased apoptosis of hepatic NKT cells. NE treatment inhibits apoptosis and restores hepatic NKT cells. In ob/ob mice with reduced hepatic NKT cells, hepatic T and NKT cells produce excessive T helper (Th)-1 proinflammatory cytokines and the liver is sensitized to LPS toxicity. NE treatment decreases Th-1 cytokines, increases production of Th-2 cytokines, and reduces hepatotoxicity. Studies of CD1d-deficient mice, which lack the receptor required for NKT cell development, demonstrate that they are also unusually sensitive to LPS hepatotoxicity. In conclusion, low NE activity increases hepatic NKT cell apoptosis and depletes liver NKT cells, promoting proinflammatory polarization of hepatic cytokine production that sensitizes the liver to LPS toxicity.     

Dietary habits and behaviors associated with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)is one of the most frequent causes of health problems in Western(industrialized)countries.Moreover,the incidence of infantile NAFLD is increasing,with some of these patients progressing to nonalcoholic steatohepatitis.These trends depend on dietary habits and life-style.In particular,overeating and its associated obesity affect the development of NAFLD.Nutritional problems in patients with NAFLD include excess intake of energy,carbohydrates,and lipids,and shortages of polyunsaturated fatty acids,vitamins,and minerals.Although nutritional therapeutic approaches are required for prophylaxis and treatment of NAFLD,continuous nutrition therapy is difficult for many patients because of their dietary habits and lifestyle,and because the motivation for treatment differs among patients.Thus,it is necessary to assess the nutritional background and to identify nutritional problems in each patient with NAFLD.When assessing dietary habits,it is important to individually evaluate those that are consumed excessively or insufficiently,as well as inappropriate eating behaviors.Successful nutrition therapy requires patient education,based on assessments of individual nutrients,and continuing the treatment.In this article,we update knowledge about NAFLD,review the important aspects of nutritional assessment targeting treatment success,and present some concrete nutritional care plans which can be applied generally.     

Dietary approach in the treatment of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) has been identified as one of the most prevalent chronic liver disease in adults and children populations. NAFLD is usually associated with the metabolic syndrome(MS), which is chiefly related to insulin resistance and its consequences. Insulin resistance has a crucial role in the pathogenesis of hepatic steatosis and potentially nonalcoholic steatohepatitis(NASH). Because of the contemporary epidemics of MS and obesity, the burden of NAFLD is also expected to rise. Unhealthy diets, such as the so-called western diet, are enriched in fructose, trans-fatty acids and saturated fat and seem to be associated with the development of NAFLD. In human studies, certain dietary sugars, particularly fructose, are used as a substrate for lipogenesis leading to hepatic fatty infiltration, inflammation, and possibly fibrosis. Other investigations have shown that fat consumption especially cholesterol and trans/saturated fatty acids are also steatogenic and seem to increase visceral adiposity. The identification of specific dietary components that favor the development of NASH could be important for the management of this disorder. This review focuses on the effects of different dietary approaches to prevent and treat NAFLD emphasizing the macronutrients and energy composition.     

Impaired dendritic cell functions disrupt antigen-specific adaptive immune responses in mice with nonalcoholic fatty liver disease

Background/aims

The magnitude of antigen-specific immunity was assessed in a murine model of nonalcoholic fatty liver diseases (NAFLD). Because antigen-specific immunity was diminished in NAFLD mice, the underlying mechanisms were evaluated through analysis of the functions of antigen-presenting dendritic cells (DC) and other immunocytes.

Methods

For 12 weeks, NAFLD mice received a high-fat (60%) and high-calorie (520 kcal/100 g) diet. C57BL/6 mice (controls) received a standard diet. NAFLD mice and control mice were immunized with hepatitis B vaccine containing hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg). Antibody to HBsAg (anti-HBs), HBsAg and HBcAg-specific cellular immune response and functions of whole spleen cells, T lymphocytes, B lymphocytes and spleen DCs of NAFLD and control mice were assessed in vitro.

Results

Levels of anti-HBs and the magnitude of proliferation of HBsAg and HBcAg-specific lymphocytes were significantly lower in NAFLD mice than control mice (P < 0.05). The spleen cells of NAFLD mice produced significantly higher levels of inflammatory cytokines (P < 0.05) and exhibited significantly increased T cell proliferation compared with control mice (P < 0.05). However, the antigen processing and presenting capacities of spleen DCs were significantly decreased in NAFLD mice compared with control mice (P < 0.05). Palmitic acid, a saturated fatty acid, caused diminished antigen processing and presenting capacity of both murine and human DCs.

Conclusions

Nonalcoholic fatty liver disease mice exhibit decreased magnitudes of antigen-specific humoral and cellular immune responses. This effect is mainly, if not solely, due to impaired antigen processing and presentation capacities of DC.     

内源性大麻系统与非酒精性脂肪肝

非酒精性脂肪肝（NAFLD）是一种以肝脏脂肪浸润、肝细胞炎症坏死为特征的慢性疾病。Nayak等、报道大约2／3的隐匿性肝硬化患者是由非酒精性脂肪肝所致。随着我国大众营养条件改善,生活习惯改变,NAFLD发病率逐年上升。     

Risk factors associated with nonalcoholic fatty liver disease and its relationship with the hepatic histological changes

OBJECTIVE: The objective of this study is to determine the association between risk factors and nonalcoholic fatty liver disease (NAFLD), and to establish the relationship between risk factors and hepatic histological changes in obese women. METHODS: A case-control design study. Women with NAFLD (cases) were compared with a control group of obese women without NAFLD matched by age, body mass index, waist circumference, and body fat. Irrespective of serum aminotransferases levels, diagnosis of NAFLD was established by the presence of type II diabetes, hypertriglyceridemia, and ultrasonographic changes of hepatic steatosis. Diagnosis of nonalcoholic steatohepatitis was performed by a liver biopsy. Women with an aspartate aminotransferase/alanine aminotransferase (ALT) ratio of at least 1 underwent liver biopsy. Alcohol consumption, hepatitis, and drugs that promote cholestasis or liver injury were the exclusion criteria. Multiple regression analysis was used to compute the association between the risk factors and NAFLD, and Spearman's analysis was used to examine its relationship with histological hepatic changes. RESULTS: A total of 108 obese women were enrolled. The frequency of high blood pressure, hypertriglyceridemia, and diabetes was similar between the groups. ALT (54.4+/-33.3 and 39.8+/-29.8, P=0.03) but not aspartate aminotransferase (45.4+/-23.1 and 36.7+/-21.2, P=0.06) was significantly higher in the women with NAFLD. The multivariate regression analysis showed a significant association of ALT (odds ratio 2.7; 95% confidence interval, 1.3-10.4), but not other variables with NAFLD. Type II diabetes was strongly correlated with ballooning and inflammation, and ALT with inflammation and fibrosis. CONCLUSION: Obese women with similar metabolic alterations exhibit different hepatic outcomes. Elevation of ALT, but not other risk factors, was associated with NAFLD. Diabetes and ALT correlate with histological hepatic changes.     

Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease

AIM: To evaluate the noninvasive parameters and hepatic fibrosis scores in obese children with nonalcoholic fatty liver disease (NAFLD).METHODS: A total of 77 children diagnosed with NAFLD via liver biopsy were included and divided into 2 subgroups according to the histopathologic staging of hepatic fibrosis: mild (stage 0-1) vs significant fibrosis (stage 2-4). Clinical and laboratory parameters were evaluated in each patient. The aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST/platelet ratio index (APRI), PGA index, Forns index, FIB-4, NAFLD fibrosis score, and pediatric NAFLD fibrosis index (PNFI) were calculated.RESULTS: No clinical or biochemical parameter exhibited a significant difference between patients with mild and significant fibrosis. Among noninvasive hepatic fibrosis scores, only APRI and FIB4 revealed a significant difference between patients with mild and significant fibrosis (APRI: 0.67 ± 0.54 vs 0.78 ± 0.38, P = 0.032 and FIB4: 0.24 ± 0.12 vs 0.31 ± 0.21, P = 0.010). The area under the receiving operating characteristic curve of FIB4 was 0.81, followed by Forns index (0.73), APRI (0.70), NAFLD fibrosis score (0.58), AST/ALT ratio (0.53), PGA score (0.45), and PNFI (0.41).CONCLUSION: APRI and FIB4 might be useful noninvasive hepatic fibrosis scores for predicting hepatic fibrosis in children with NAFLD.     

非酒精性脂肪性肝病的饮食治疗

随着高脂肪高热量膳食的盛行、生活节奏的加快和多坐少动生活方式的流行,肥胖、糖尿病及其相关非酒精性脂肪性肝病（Nonalcoholic fatty liver diseases,NAFLD）已成为愈来愈重要的慢性非传染性流行病。在重度肥胖症患者中,NAFLD的发病率高达90%,其中20%～30%为非酒精性脂肪性肝炎（NASH）,高达8%患者已发展至肝硬化阶段。     

非酒精性脂肪性肝病发病相关危险因素分析

目的分析体检人群非酒精性脂肪性肝病（NAFLD）发生的危险因素。方法2016年1月~2017年1月对在河南省省直第二医院进行健康体检的人群采用Logistic回归分析与NAFLD发生的危险因素。结果在1421名体检人群中,检出NAFLD 245例（17.2%）,男性NAFLD发病率为23.9%,明显高于女性的8.5%（P<0.05）;单因素分析显示NAFLD患者性别、血清总胆固醇、甘油三酯、低密度脂蛋白、空腹血糖、谷丙转氨酶、γ-谷氨酰转肽酶、体质指数水平、伴有高血压、冠心病、高尿酸血症、糖尿病和吸烟的比例显著高于非NAFLD人群;在校正混杂因素后,经Logistic多因素回归分析显示,血清TG 、TC、ALT、GGT和BMI水平高、伴有糖尿病和高血压为NAFLD发生的独立危险因素。结论肥胖、高血压、糖尿病和高脂血症为NAFLD发病的危险因素,减轻体质量,维持正常血脂和血糖水平是防治NAFLD的关键措施。     

Dyslipidemia in patients with nonalcoholic fatty liver disease

Patients with nonalcoholic fatty liver disease (NAFLD) often have dyslipidemia along with other features of metabolic syndrome such as obesity, diabetes mellitus, and hypertension. The dyslipidemia in NAFLD is characterized by increased serum triglycerides, increased small, dense low-density lipoprotein (LDL nontype A) particles, and low high-density lipoprotein (HDL) cholesterol. The pathogenesis of dyslipidemia in NAFLD is not well understood, but it is likely related to hepatic overproduction of the very low-density lipoprotein particles and dysregulated clearance of lipoproteins from the circulation. There is unequivocal evidence that cardiovascular disease is the most common cause of mortality in patients with NAFLD. Aggressive treatment of dyslipidemia plays a critical role in the overall management of patients with NAFLD. Statins are the first-line agents to treat high cholesterol and their dosage should be adjusted based on achieving therapeutic targets and tolerability. Although all statins appear to be effective in improving cholesterol levels in patients with NAFLD, there is more experience with atorvastatin in patients with NAFLD; furthermore, it is the only statin to date to show a reduced cardiovascular morbidity in patients with NAFLD. The risk for serious liver injury from statins is quite rare and patients with NAFLD are not at increased risk for statin hepatotoxicity. Omega-3 fatty acids are perhaps the first choice to treat hypertriglyceridemia because of their safety, tolerability, and efficacy in improving serum triglycerides, as well as their potential to improve liver disease.     

Irisin in patients with nonalcoholic fatty liver disease

Objective

Irisin is a recently discovered myokine proposed to increase thermogenesis-related energy expenditure and improve metabolism. We aimed to comparatively evaluate serum irisin levels in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) vs. controls and study their association with disease severity.

Methods

Fifteen and 16 consecutively enrolled patients with biopsy-proven nonalcoholic simple steatosis (NAFL) and steatohepatitis (NASH), respectively, and 24 lean and 28 obese controls without NAFLD were recruited. Irisin, established adipokines and biochemical tests were measured.

Results

Serum irisin levels were statistically different in obese controls (33.7 ± 2.7 ng/mL; p < 0.001) and patients with NAFL (30.5 ± 1.5 ng/mL; p < 0.001) and NASH (35.8 ± 1.9 ng/mL; p = 0.001) compared with lean controls (47.7 ± 2.0 ng/mL), but were similar among patients with NAFL, NASH and obese controls. This difference remained significant after adjustment for body mass index (or waist circumference), gender, age, insulin resistance (assessed by HOMA-IR or QUICKI), exercise and time since blood collection. Serum leptin and adiponectin, but not irisin, levels were independently from BMI correlated with insulin resistance and cardiometabolic factors. Serum irisin tended to be higher in patients with (36.7 ± 2.4 ng/mL) than without (30.8 ± 1.2 ng/mL; p = 0.02) portal inflammation and independently associated with the latter; these data need to be confirmed by future studies.

Conclusions

Serum irisin levels differ between lean controls and obese controls or NAFLD patients. Despite similar circulating irisin levels between NAFL and NASH groups, irisin may be independently and positively associated with the presence of portal inflammation. Future clinical and mechanistic studies are needed to confirm and extend these data.     

非酒精性脂肪性肝病与高尿酸血症

<正>非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是临床最常见的慢性肝病之一,我国成年人NAFLD患病率超过15%,并且呈现不断上升趋势[1]。近年来,越来越多的研究报道,高尿酸血症与NAFLD密切相关。临床研究发现,NAFLD患者常合并高尿酸血症,并且高尿酸血症显著增加NAFLD的发病风险。动物实验结果表明,高尿酸能引发NAFLD发生,降尿酸干预可有效减轻NAFLD     

Biomarkers in nonalcoholic fatty liver disease

BACKGROUND:

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition characterized by insulin resistance, type 2 diabetes and fat accumulation in the liver that may cause hepatic inflammation and progressive scarring leading to nonalcoholic steatohepatitis (NASH) and irreversible liver damage (cirrhosis). As a result, there has been increased recognition of the need to assess and closely monitor individuals for risk factors of components of NAFLD and NASH, as well as the severity of these conditions using biomarkers.

AIM:

To review the biomarkers used to diagnose and define the severity of NAFLD and NASH.

METHODS:

A comprehensive PubMed and Google Scholar literature search was performed using the terms “non-alcoholic fatty liver disease”, “non-alcoholic steatohepatitis”, as well as the name of each biomarker known to be used. Articles indexed between 2004 and 2014 were used. Each author read the publications separately and the results were discussed.

RESULTS:

Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression or both. Serum biomarkers, including total cholesterol, triglycerides, insulin resistance and C-peptide, have been used for many years. Emerging biomarkers, such as apolipoprotein A1, apolipoprotein B, leptin, adiponectin, free fatty acids, ghrelin and tumour necrosis factor-alpha, have been proposed as tools that could provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of cell death and mitochondrial dysfunction (cytokeratins) represent powerful predictors of risk. For biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in sex and ethnic origin are a necessity.

CONCLUSIONS:

The present review attempts to provide a comprehensive analysis of the emerging risk biomarkers of NAFLD and NASH, and to use the clinical significance and analytical considerations of each biomarker pointing out sentinel features of disease progression.     

Leptin in nonalcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition associated with obesity and insulin resistance (IR). Leptin plays a key role in the control of energy balance, and insulin sensitivity. In this study, we aimed to examine whether serum leptin levels correlate with insulin resistance, oxidative stress parameters and the severity of histological changes in NAFLD. Methods: Fifty-two patients (M/F: 28/24) with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied. Serum leptin levels were measured by radioimmunoassay. HOMA (homeostasis model assessment) IR index was calculated. Comparisons between the patients with NAFLD and non-alcoholic steatohepatitis (NASH) were performed using the Student’s t test. Multivariate regression analysis and the area under the receiver operating characteristic (ROC) curve were used to identify the independent predictors for NASH. Results: We found no association between serum leptin, fasting insulin levels, and oxidative stress parameters. ROC curve and multiple regression analysis revealed no association between the severity of histological changes and serum leptin levels. During six months followed-up period only NASH group with elevated leptin levels had significant reductions of ALT and AST values (p = 0.03, and 0.005, respectively). Conclusion: Our findings show a preventive effect of leptin against progressive liver injury in NAFLD.     

Mitochondria in nonalcoholic fatty liver disease

Nonalcoholic fatty liver (NAFL) is associated with fundamental issues of fat metabolism and insulin resistance. These abnormalities have been linked to impairment of ATP homeostasis, and a growing body of literature has reported mitochondrial abnormalities in various forms of hepatic steatosis. The changes are evident as structural abnormalities, including greatly increased size and the development of crystalline inclusions, and are usually regarded as pathologic, reflecting either a protective or degenerative response to injury. Although the relationships between structural changes,decreased mitochondrial function, and disease states are becoming clearer, the molecular basis for the perturbations is not well understood.Oxidative damage is the most likely causative process and may result in alterations of mitochondrial DNA (mtDNA), stimulated apoptotic pathways, and increased propensity for necrosis.Overall mitochondrial health likely depends on multiple factors including the integrity of the mtDNA, the composition of cellular lipids, lipoprotein trafficking, the balance of pro- and antioxidant factors, and the metabolic demands placed on the liver. Mitochondrial dysfunction may play a role in numerous clinical conditions associated with NAFL, such as hepatocellular carcinoma, lipodystrophy,age-related insulin resistance, gut dysmotility, cryptogenic cirrhosis, a mild form of gaze palsy, and possibly other more severe neurodegenerative diseases. The prominent role of mitochondrial dysfunction in NAFL provides a new and exciting paradigm in which to view this disorder, its complications, and potential dietary and pharmacologic intervention.     

Imaging techniques for assessing hepatic fat content in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD), an emerging clinical entity with worldwide recognition, is today the most common cause of abnormal liver function tests among adults in the United States. In Mexico City, its prevalence has been reported by our group to be around 14%, but its incidence is higher in the hispanic population in the United States (hispanic population 45%, white population 33%, black population 24%). The main issues in the diagnosis, follow-up, and management of NAFLD are our limited understanding of its pathophysiology and the difficulties involved in developing a noninvasive diagnostic method. Several imaging techniques can detect fatty infiltration of the liver, each with its own advantages and disadvantages. Ultrasound is still in the first option for diagnosis, but its accuracy depends on the operator and the patient's features. Computed tomography can detect hepatic fat content, but only at a threshold of 30%, and it involves ionizing radiation. Magnetic resonance (MR) spectroscopy is probably the most accurate and fastest method of detecting fat, but it is expensive and the necessary software is still not easily available in most MRI units. MR elastography, a new technique to detect liver stiffness, has not been demonstrated to detect NAFLD, and is still undergoing research in patients with hepatitis and cirrhosis. In conclusion, all these imaging tools are limited in their ability to detect coexisting inflammation and fibrosis. In this review, we discuss the radiological techniques currently used to detect hepatic fat content.